The major responsibility for carrying out the functions of the immune system is born by white blood cells called lymphocytes. Lymphocytes can be categorized into two major classes, i.e., T cells and B cells. T cells (i.e., T-lymphocytes) originate from stem cells in the bone marrow, develop in the thymus gland and secrete lymphokines. B cells (i.e., B-lymphocytes) originate from stem cells in the bone marrow and are the source of antibodies. In fact, B cells generate five different types of antibodies including IgM, IgG, IgA, IgD and IgE. These antibodies can neutralize substances that can trigger an immune response, i.e., antigens, by attaching to specific sites on the antigens in order to block them. IgM is the largest antibody and the primary antibody against A and B antigens on red blood cells. Structurally, IgM forms polymers where multiple immunoglobulins are covalently linked together with disulfide bonds, primarily as a pentamer but also as a hexamer. IgM has a molecular mass of approximately 900 kDa in its pentameric form. Because each monomer has two antigen binding sites, a pentameric IgM has ten (10) binding sites.
Numerous diseases are associated with altered or dysfunctional B cells including, but not limited to, autoimmune diseases and cancer. The proliferation and differentiation of B cells is regulated by receptors localized on the cell surface. The engagement of these receptors induces the activation of intracellular signaling proteins that transmit the receptor signals to specific targets inside the cell that control the cellular responses. Many signaling proteins are the products of oncogenes and many oncogenes are associated with tumorgenesis. The molecular mechanisms of signaling pathways that control the proliferation and differentiation of B cells are still being studied (Jumaa et al. (2005) Annu. Rev. Immunol. 23:415-445).
An example of a disease involving neoplastic B lymphocytes is acute lymphoplastic leukemia (ALL). Some progress in combating this disease is due to intensification of chemotherapy, as well as better supportive care for both, pediatric and adult ALL. While the risk of relapse is lower in the pediatric population, both pediatric and adult patients face dire outcomes if the disease recurs. Less than one third of children and few adults with relapsed ALL survive this disease despite the use of aggressive regimens and stem cell transplantation. Novel therapies are therefore needed that reach beyond conventional chemotherapy. For ALL, there is preclinical and early clinical data with a variety of monoclonal antibodies including rituximab, epratuzumab and gemtuzumab, suggesting that the use of monoclonal antibodies alone or in combination with standard chemotherapy is a viable treatment option.
U.S. Pat. No. 5,593,676 describes ways of inducing cell death in neoplastic B cells by using reagents that bind a specific B cell epitope called cell death inducing molecule (CDIM). Herein, the B cell specific oligosaccharide epitope CDIM is used as a neoplastic B cell marker. IgM antibodies specific for this marker are administered to a host in vivo to induce death in neoplastic B cells. The same concept can be applied in ex vivo clinical situations to selectively remove B cells. A human monoclonal antibody (i.e., MAb 216), which recognizes the B cell epitope CDIM is cytotoxic to neoplastic and normal B cells and binds all CD19+ and CD20+ B lymphocytes in human peripheral blood and spleen. Furthermore, MAb 216 does not distinguish B cells by the isotype expressed, binding IgG+ and IgM+ cells with equal intensity. MAb 216 also binds all B cells regardless of their CD5 expression. Hence, MAb 216, is useful in diagnosis and therapy. See, also Bhat et al. (2000), Scand. J. Immunol. 51:134-140.
However, there remains a need in the art to identify antibodies that are specific for B cells to selectively kill and/or remove them from the host with reduced off-target binding and/or tissue damaging side effects. Cancer therapy still has a tremendous need for such therapeutic antibodies. The present application addresses this need.